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Chemical genomics: Functional analysis of orphan nuclear receptors in the regulation of bile acid metabolism
Author(s) -
Willson Timothy M.,
Jones Stacey A.,
Moore John T.,
Kliewer Steven A.
Publication year - 2001
Publication title -
medicinal research reviews
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.868
H-Index - 130
eISSN - 1098-1128
pISSN - 0198-6325
DOI - 10.1002/med.1023
Subject(s) - pregnane x receptor , nuclear receptor , lithocholic acid , bile acid , farnesoid x receptor , biochemistry , g protein coupled bile acid receptor , receptor , functional genomics , biology , liver x receptor , chemistry , transcription factor , gene , genomics , genome
Abstract Chemical genomics is the name we have given to the analysis of gene function through use of small molecule chemical tools. Orphan nuclear receptors are ideally suited to this technique of functional analysis, since their activity as transcription factors is regulated by small hydrophobic ligands. GW4064 is a potent and selective nonsteroidal ligand for the nuclear bile acid receptor FXR (NR1H4). Using GW4064 as a chemical tool, we have identified genes regulated by FXR in the liver, including those involved in bile acid synthesis and transport. We have also discovered that PXR (NR1I2) is a lithocholic acid receptor that controls the biosynthesis and metabolism of bile acids. Together FXR and PXR cooperate to control biliary and urinary bile acid excretion. These functions suggest that potent PXR and FXR ligands may offer a new approach to the treatment of cholestatic liver disease. © 2001 John Wiley & Sons, Inc. Med Res Rev, 21, No. 6, 513–522, 2001